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Your search keyword '"Pérez‐Morga, D."' showing total 2 results
Start Over Author "Pérez‐Morga, D." Journal nature
2 results on '"Pérez‐Morga, D."'

1. Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis.

Author

Pastushenko I, Mauri F, Song Y, de Cock F, Meeusen B, Swedlund B, Impens F, Van Haver D, Opitz M, Thery M, Bareche Y, Lapouge G, Vermeersch M, Van Eycke YR, Balsat C, Decaestecker C, Sokolow Y, Hassid S, Perez-Bustillo A, Agreda-Moreno B, Rios-Buceta L, Jaen P, Redondo P, Sieira-Gil R, Millan-Cayetano JF, Sanmatrtin O, D'Haene N, Moers V, Rozzi M, Blondeau J, Lemaire S, Scozzaro S, Janssens V, De Troya M, Dubois C, Pérez-Morga D, Salmon I, Sotiriou C, Helmbacher F, and Blanpain C

Subjects
Adaptor Proteins, Signal Transducing metabolism, Animals, Cadherins genetics, Cadherins metabolism, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Disease Progression, Enhancer of Zeste Homolog 2 Protein metabolism, Epithelial Cells metabolism, Epithelial Cells pathology, Epithelial-Mesenchymal Transition drug effects, Gene Expression Regulation, Neoplastic, Humans, Hyaluronan Receptors metabolism, Lung Neoplasms genetics, Lung Neoplasms pathology, Mesoderm metabolism, Mesoderm pathology, Mice, Neoplasm Metastasis drug therapy, Neoplasms drug therapy, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Phenotype, Phosphoproteins analysis, Phosphoproteins metabolism, Proteomics, SOXB1 Transcription Factors metabolism, Signal Transduction, Skin Neoplasms genetics, Skin Neoplasms pathology, Transcription Factors metabolism, YAP-Signaling Proteins, Zinc Finger E-box-Binding Homeobox 1 metabolism, src-Family Kinases metabolism, Cadherins deficiency, Epithelial-Mesenchymal Transition genetics, Gene Deletion, Neoplasm Metastasis genetics, Neoplasms genetics, Neoplasms pathology
Abstract

FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers 1-5 . However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.

Published
2021
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2. Mechanism of Trypanosoma brucei gambiense resistance to human serum.

Author

Uzureau P, Uzureau S, Lecordier L, Fontaine F, Tebabi P, Homblé F, Grélard A, Zhendre V, Nolan DP, Lins L, Crowet JM, Pays A, Felu C, Poelvoorde P, Vanhollebeke B, Moestrup SK, Lyngsø J, Pedersen JS, Mottram JC, Dufourc EJ, Pérez-Morga D, and Pays E

Subjects
Africa, Animals, Animals, Genetically Modified, Apolipoprotein L1, Apolipoproteins antagonists & inhibitors, Apolipoproteins toxicity, Cell Membrane chemistry, Cell Membrane metabolism, Cysteine Proteases metabolism, Haptoglobins metabolism, Hemoglobins metabolism, Hemolysis, Humans, Hydrophobic and Hydrophilic Interactions, Lipid Metabolism, Lipoproteins, HDL antagonists & inhibitors, Lipoproteins, HDL chemistry, Lipoproteins, HDL toxicity, Parasites pathogenicity, Parasites physiology, Protein Structure, Secondary, Serum chemistry, Serum parasitology, Trypanosoma brucei gambiense drug effects, Trypanosoma brucei gambiense pathogenicity, Trypanosomiasis, African parasitology, Variant Surface Glycoproteins, Trypanosoma chemistry, Variant Surface Glycoproteins, Trypanosoma metabolism, Apolipoproteins blood, Apolipoproteins metabolism, Lipoproteins, HDL blood, Lipoproteins, HDL metabolism, Trypanosoma brucei gambiense physiology
Abstract

The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1). Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5), TLF-2 enters trypanosomes independently of TbHpHbR (refs 4, 5). APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic β-sheet of the T. b. gambiense-specific glycoprotein (TgsGP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa.

Published
2013
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